pediatric acute liver failure

D Lenz et al. Hepatology 2024; 79: 1075-1087. Open Access! Genetic landscape of pediatric acute liver failure of indeterminate origin

Background: ” In US and European cohorts, the underlying etiology [of PALF] remained unclear in about half of cases, hampering clinical management including disease-specific therapies, particularly decision-making regarding liver transplantation.” The associated editorial (pg 970-972) by Squires and Horslen note that standardized evaluation of PALF can lower the indeterminate cases to ~30%.

This study had 96 authors! (I think). In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF.

Key findings:

Whole-exome sequencing (WES) established a genetic diagnosis in 37% of cases (97/260)
Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%)
Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. The underlying pathophysiologies in those with abnormal WES were mitochondrial diseases (45%) and disorders of vesicular trafficking (28%)

Discussion points:

55% of patients in this series had no evidence of an underlying genetic disorder. “According to Squires et al,³² the fraction of PALF cases with unknown etiology is particularly high in the first 3 years of life, which is the age range in which our study demonstrates the highest molecular diagnostic yield by WES.”
Rapid turnaround of genetic testing is essential in order to have an important clinical impact. A “short period of time as the clinical situation typically is critical and decisions are time-sensitive.” Yet the editorial noted that “rapid” testing in most laboratories require 1-6 months.

My take: Genetic testing is important for indeterminate PALF and may help in determining whether to proceed with a liver transplant.

D Bonser et al. J Pediatr 2023; 260: 113534. Rapid Genome Sequencing Diagnosis in Pediatric Patients with Liver Dysfunction

In this retrospective study with 18 pediatric patients (2019-2021) who presented with pediatric acute liver dysfunction, the authors examined the yield of rapid whole genome sequencing (rWGS). Key findings:

Median turnaround was 8 days. In patients with a diagnostic study, an initial report was received in a median of 4 days compared to 10 days with a non-diagnostic study.
7 patients (39%) had diagnostic results including two with ornithine transcarbamylase deficiency, one with Wilson’s disease, one with PFIC type 1, one with infantile liver failure syndrome 2 (due to NBAS gene), one with GSD type 4, and one with infantile liver failure syndrome 1 (due to LARS gene).
Five of these patients with abnormal rWGS had liver transplantation evaluation/listing after the test results were received

One annoying aspect of the report is the authors’ attempt to suggest that the diagnostic yield should have been higher if they excluded four patients subsequently thought to have liver dysfunction due to environmental exposures. In a retrospective study, it is easy to second-guess and say that the test could have been used more selectively.

My take: This study shows that rapid whole genome sequencing is a very valuable part of the evaluation of children with severe liver dysfunction. Turnaround times have improved considerably.

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Tag Archives: pediatric acute liver failure

Genetic Testing for Pediatric Acute Liver Failure of Indeterminate Origin

Rapid Genetic Testing in Liver Failure